Inflammaging mediates testosterone declines in men while maintaining high testosterone increases mortality risk

Later life is accompanied by testosterone declines alongside the development of chronic inflammation, termed inflammaging(definition). A new theoretical model posits these processes are related through an energetic trade-off. As somatic damage accumulates, this should chronically activate the energetically costly inflammatory response. As an energy conserving response to promote cellular repair, testosterone production is expected to be suppressed. Consistent with this model, we find that markers of inflammaging, including IL-6 and GDF-15, mediate age-related testosterone declines in a large sample of male participants from the UK Biobank (n = 18,347, mean age 57 years, range 40-70). GDF-15, a marker of chronic inflammation and a key metabolic stress signaling protein, was the strongest predictor and mediator of testosterone declines. Further, individuals with high testosterone given their health and level of inflammation showed elevated mortality risk over follow up, consistent with a trade-off between maintenance and reproduction. Our results highlight the importance of considering energetic trade-offs to understand later life testosterone declines. They also highlight the importance of alleviating cellular damage that augments inflammaging and its down-stream hormonal effects. Finally, our study raises concern for exogenous testosterone therapies in the context of chronic inflammation, which could increase mortality risk. <h4>Graphical Abstract</h4>